A study from researchers at KAIST (Korea Advanced Institute of Science and Technology) is providing new insights into a cellular energy pathway that has been linked to longer lifespan. The research, conducted in human cells and roundworms, raises the prospect of anti-aging therapeutics that can extend lifespan by activating this pathway.
AMPK (adenosine monophosphate-activated protein kinase) is an enzyme that acts as a metabolic master switch. It has been described as a “magic bullet” protein, conferring broad beneficial health effects, from improving cardiovascular health to extending lifespan. It is activated in response to low cellular energy levels, as is often seen during exercise or periods of caloric restriction.
An increasing volume of study has found activating AMPK in animal models leads to notable increases in lifespan, prompting a surge in research investigating this enzyme.
The new KAIST study focused on this pathway in a tiny roundworm, caenorhabditis elegans (C. elegans), often used by researchers as a model to investigate lifespan. The researchers discovered an enzyme called VRK-1 works in tandem with AMPK to regulate cellular energy processes.
Boosting VRK-1 activity in the roundworms extended the organism’s lifespan by stimulating AMPK activity, and inhibiting the enzyme reduced its lifespan. Moving to laboratory cell tests the researchers verified this VRK-1 to AMPK mechanism does seem to occur in human cells, suggesting it is possible the lifespan-extending results may be replicated in human subjects.
“This raises the intriguing possibility that VRK-1 also functions as a factor in governing human longevity, and so perhaps we can start developing longevity-promoting drugs that alter the activity of VRK-1,” explains Seung-Jae V. Lee, who lead the new research.
It is still extraordinarily early days for the research, and the next steps will be to explore the effects of modulating VRK-1 activity in more complex animal models such as rodents. Lee says the success in replicating this VRK-1 to AMPK mechanism in human cells suggests the pathway may be relevant in a number of complex organisms, but it is still unclear how this could be harnessed for therapeutic outcomes.
What are the stressors which can affect cellular aging and shortening of telomeres? Blackburn listed a few of them such as stress hormones, oxidative stress and inflammatory stress. All of these stressors cause stress on a molecular level, which means they can damage proteins and other essential components of a cell. Oxidative stress, the excess production of reactive oxygen species oxidizes proteins, disrupting their structure and function to the extent that oxidized proteins become either useless or even harmful. Inflammatory stress refers to excessive inflammation which transcends the normal inflammatory response of cells from which they can recover. Prolonged inflammation, for example, can cause cells to activate a cell-death program. Recent studies in mice have shown that activation of inflammation pathways in the brain can suppress cognitive function, muscle strength and overall longevity. Blackburn also pointed out that stressors are often interconnected. Prolonged elevation of stress hormones or prolonged inflammation can increase oxidative stress. The higher the level of these stressors, the more prematurely cells will age. This means that the body of a person in their 30s or 40s exposed to high levels of inflammation or oxidative stress may already numerous cells showing signs aging.
How do these stressors lead to premature aging? Shortening of telomeres could be one answer. If cells are chronically inflamed due to autoimmune diseases or inflammation-associated diseases such as obesity and atherosclerosis then they have to be continuously replaced by cell division which shortens telomeres. However, telomere shortening is not the only route to cell aging. Aging research groups have uncovered multiple additional pathways which can accelerate the premature aging of cells without necessarily requiring the shortening of telomeres. Inflammation or oxidative stress can activate certain aging pathways such as the aging regulator p16INK4a. Our own work has shown that an inflammatory cytokine can convert highly regenerative blood vessel progenitor cells into aged cells which no longer replicate by activating p16INK4a, and that this occurs without affecting telomere length. Judith Campisi from the Buck Institute of Aging as well as several other researchers have uncovered an important vicious cycle: Once cells begin aging, they themselves release inflammatory proteins which in turn can activate aging in neighboring cells, thus setting a self-reinforcing cascade of aging in motion.